Monocytic Differentiation and AHR Signaling as Primary Nodes of BET Inhibitor Response in Acute Myeloid Leukemia

Abstract

is a member of Scientific Advisory Boards for Kodikaz Therapeutic Solutions, Coherus Biosciences, and Zenshine Pharmaceuticals, and is an inventor on multiple patients related to CD47 cancer immunotherapy licensed to Gilead.

Integrative analysis of drug response and clinical outcome in acute myeloid leukemia

“…We and others have observed that drug response patterns in AML are sometimes correlated with maturation state of AML tumor cells, with certain drugs exhibiting stronger efficacy against tumors with less differentiated cell state (e.g., BCL2i, cyclin dependent kinase 4/6 [CDK4/6]i; Kuusanmaki et al, 2020;Majumder et al, 2020;Pei et al, 2020;Romine et al, 2021;Zhang et al, 2020) and others showing better efficacy against tumors with more differentiated state (e.g., bromodomain containing 4 [BRD4/BET] i, mitogen-activated protein kinase kinase [MAPKK/MEK]i; Romine et al, 2021;White et al, 2021). Analytical approaches can facilitate the deconvolution of deep-sequencing data to infer proportions of distinct cell types (Avila Cobos et al, 2018), and single-cell sequencing technology has recently defined gene expression patterns for six distinct cell types in AML (hematopoietic stem cell [HSC]-like, progenitor-like, granulocyte-monocyte progenitor [GMP]-like, promonocyte-like, monocyte-like, and conventional dendritic cell [cDC]-like types; Van Galen et al, 2019).…”

High-Throughput CRISPR Screening in Hematological Neoplasms

“…Since AML remains an incurable disease for the majority of patients, great efforts have focused to develop novel inhibitors during the last decade [ 201 ]. In this sense, CRISPR screening studies have helped to anticipate potential mechanisms of resistance for some of these new therapeutic approaches in AML [ 44 , 73 , 120 , 202 ].…”

“…Similar approaches have also revealed metabolic genes capable of influencing cellular commitment to apoptosis and sensitizing AML cells to venetoclax [ 82 , 85 ]. Finally, CRISPR high-throughput approaches have anticipated gene determinants to enhance the sensitivity of small molecules under development for AML treatment [ 45 , 73 , 242 ].…”

“…Interestingly, the loss-of-function of the BAX gene has been commonly involved in venetoclax resistance in both CLL or AML diseases [ 63 , 72 ], DCK disruption in the resistance of cytarabine for AML or ALL [ 42 , 49 ] and CSN subunits of the CSN9 complex have been related with IMiDs resistance in MM or lymphoma [ 56 , 90 , 189 ]. Moreover, we can anticipate the resistance mechanisms of drugs under investigation through CRISPR approaches before their approval and the molecular characterization of a cohort of patients treated with novel drugs (for example, BET inhibitors, HSP90 inhibitors…) [ 44 , 73 , 120 , 202 ]. Taking into account that novel therapies are continuously emerging in hemato-oncology, we therefore envision that CRISPR screening will continue to have a role in the era of targeted therapy and immunotherapy.…”

Utilization of CRISPR-Mediated Tools for Studying Functional Genomics in Hematological Malignancies: An Overview on the Current Perspectives, Challenges, and Clinical Implications

“…In vitro CRISPR screens were also utilized to identify genes which sensitizes AML cells to double-negative T cells (DNTs) therapies for effective patient treatments (Soares et al, 2021). Moreover, researchers have also studied the genetic mechanisms that undermine the effectiveness of BCL2 inhibitors in AML treatments using CRISPR-based genome-wide screening (Romine et al, 2021). CRISPR gene knockout screens were also performed to recognize mitochondrial genes necessary for the growth of AML cells.…”